The introduction of protease inhibitors (PIs) into highly active antiretroviral therapy (HAART), a combination therapy based on co-administration of PIs with reverse-transcriptase inhibitors, has marked the beginning of a new era in HIV/AIDS chemotherapy. HAART treatment regimens have led to a significant decline in the number of deaths due to HIV infection in the developed World. Unfortunately there are a number of factors that severely limit current HAART treatment regimens. High frequency of dosing, heavy pill burden and issues of tolerability and toxicity can lead to poor adherence to treatment. The need for more potent, less toxic drug regimens is quite apparent.
It is the rapid emergence of drug resistance however, that is proving to be the most formidable problem. Mutations causing drug resistance are thought to occur spontaneously, through the recombination of mixed viral populations, and also due to drug pressure, particularly when administered at sub-standard doses. There is ample evidence that these viral strains can be transmitted. Thus, the development of new antiretroviral agents, including those able to maintain potency against resistant HIV strains has become an urgent priority.
The proteolytic enzyme, HIV-1 protease has been reported to be essential for viral assembly and maturation. As a consequence, design of specific inhibitors for HIV-1 protease has become the subject of widespread interest. In 1996, protease inhibitors (PIs) were introduced in combination with reverse transcriptase inhibitors to become highly active antiretroviral therapy (HAART). This treatment regimen significantly increased life expectancy, improved quality of life and decreased mortality and morbidity among HIV/AIDS patients. Despite these notable advances, the emergence of drug-resistant HIV-1 variants is severely limiting the efficacy of HAART treatment regimens. Therefore, development of new broad spectrum antiretroviral drugs that produce minimal adverse effects remains an important therapeutic objective for the treatment of HIV/AIDS (Wainberg, M. A.; 1998; Grabar, S.; et al., AIDS, 2000, 14, 141; Hertogs, K., 2000; the disclosure of the foregoing is incorporated herein in its entirety by reference). The entirety of the disclosures of each of the documents cited herein are also incorporated herein by reference. The structure-based design and development of a series of novel HIV-1 protease inhibitors including Darunavir, TMC-126, and GRL-06579A (compound 101) has recently been described (Surleraux, D. L. N. G.; et al., J. Med. Chem., 2005, 48, 1813; Koh, Y.; et al., Antimicrob. Agents Chemother., 2003, 47, 3123; Ghosh, A. K.; et al., Antiviral Res., 2002, 54, 29; Ghosh, A. K.; et al., Bioorg. Med. Chem. Lett., 1998, 8, 687; Yoshimura, K.; et al., J. Virol., 2002, 76, 1349). These inhibitors exhibited marked potency in enzyme inhibitory and cell culture assays. Furthermore, these inhibitors have shown activity against a broad spectrum of HIV isolates including a variety of multi-PI resistant clinical strains. Darunavir has been recently approved for the therapy of HIV/AIDS patients who are harboring drug-resistant HIV and do not respond to other antiretroviral drugs. Nevertheless, additional options are needed for the treating physician to use instead of, or in conjunction with currently known therapies.
In one embodiment, a compound of the formula
or a pharmaceutically acceptable salt thereof is described;wherein
A and B are each independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclyl, optionally substituted amino alkyl, arylalkyl, heteroarylalkyl, and arylthioalkyl, each of which is optionally substituted;
X is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
Y is C(O), SO2, or an optionally substituted alkylene;
Z is an optionally substituted C7-16 cycloalkyl, an optionally substituted C7-16 heterocycle, or a radical of the formula

where n is 0, 1, or 2;
m is 0, 1, 2, 3, or 4;
V is oxygen, optionally substituted nitrogen, or SO2;
Ra and Rb are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, and optionally substituted arylalkyl;
or Ra and Rb are taken together to form an optionally substituted heterocycle;
providing that V—Ra and the ring oxygen are not attached to the same atom;
Rc and Rd are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, hydroxyl, optionally substituted alkoxy, optionally substituted arylalkoxy, and optionally substituted amino;
W1 is a bond, an optionally substituted alkylene, or an optionally substituted nitrogen;
W2 is selected from the group of divalent radicals consisting of optionally substituted alkylene, oxygen, sulfur, optionally substituted nitrogen, SO2, and an optionally substituted heterocycle, and combinations thereof;
providing that W2 does not include —O—O— or —O—S—;
W3 is optionally substituted alkylene or oxygen;
W4 is a bond, an optionally substituted alkylene, or an optionally substituted nitrogen;
W5 is selected from the group of divalent radicals consisting of optionally substituted alkylene, oxygen, sulfur, optionally substituted nitrogen, SO2, and optionally substituted fused heterocycle;
providing that W5 does not include —O—O— or —O—S—; and providing that if all of W3, W4, and W5 are optionally substituted alkylene, at least one of Rc or Rd is hydroxyl, alkoxy, or optionally substituted amino.
In another embodiment pharmaceutical compositions are described, where the compositions include one or more of the compounds described herein in a therapeutically effective amount for treating an HIV infection, AIDS, or an AIDS-related disease. In another embodiment, the pharmaceutical compositions described herein also include one or more carriers, diluents, or excipients, or a combination thereof. In another embodiment, methods for treating a patient in need of relief from an HIV infection is described, where the methods include the step of administering to the patient a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions described herein.